dsDNA viruses

CMX001 is in development for the treatment of double stranded DNA (dsDNA) viruses in transplant recipients, representing an estimated market in excess of $1 billion. The compound has the potential to become a standard of care for "universal prophylaxis" for dsDNA viruses in immunocompromised patients due to its broad-spectrum antiviral activity.

Human cytomegalovirus (CMV) is a member of the herpesvirus family of dsDNA viruses that typically causes mild or subclinical disease, but can cause severe systemic or localized disease in immunocompromised individuals. CMV is a common virus that infects most people worldwide. In most developed countries, 40-80 percent of children are infected with CMV before puberty and exposure to the virus increases with age in the general population. Like other members of the herpesvirus group, CMV rests in the host in a latent state following primary infection. The virus can emerge from latency when the immune system becomes compromised, causing significant morbidity and mortality. Organ involvement manifestations of CMV disease include hepatitis, pneumonitis, pancreatitis, colitis, erosive gastrointestinal bleeding, meningoencephalitis, myocarditis, and chorioretinitis.

Historically, CMV-induced disease has been most frequently observed in HIV/AIDS patients, immunosuppressed transplant recipients and cancer patients receiving chemotherapy. We are initially developing CMX001 for use in transplant patients where there is a significant unmet medical need. Cytomegalovirus is present in more than two-thirds of donors and recipients prior to transplantation. In a study of transplant patients who did not receive induction therapy or CMV prophylaxis, the relative risk of overall mortality was 2.5 to 2.9 times higher than those without CMV for CMV disease and CMV infection, respectively. The burden of CMV disease in the transplant population has increased as the frequency of organ transplantation has increased. Each year more than 60,000 transplants are performed in the U.S. and Europe. Over 75 percent of these transplant recipients are at moderate-to-high risk of CMV a dsDNA viral infection adn a sizable proportion are co-infected with multiple dsDNA viruses. Organ loss and other morbidities due to CMV remain a large and costly issue.

Therapy for CMV in transplant patients may be prophylactic, preemptive or treatment of disease. Despite prophylaxis with existing drugs, often continued for 100 days, disease prevalence at six months is estimated to be from 12 to 22 percent.

The in vitro activity of CMX001 against CMV has been assessed in MRC-5 cells (a human lung fibroblast-derived cell line) and human foreskin fibroblast (HFF) cells. Depending on cell type, virus strain, and method of assay (DNA or plaque reduction), EC50 values ranged from 2 x 10-6 µM to 2.5 x 10-2 µM. In all cases, CMX001 was 2 to 5 logs more potent than cidofovir.

CMX001 is expected to have a decided advantage over current treatments for prophylaxis of CMV infection in solid organ and bone marrow transplant recipients and in cancer patients receiving myelosuppressive chemotherapy or radiation therapy based on its potential for increased potency, decreased toxicity, broader spectrum antiviral activity and favorable cross resistance profile.

Like CMV, BK virus is widespread but rarely causes disease, except in immunosuppressed or immunocompromised patients. A member of the polyomavirus family, BK virus remains latent in the kidney and urinary tract where it persists throughout a patient's lifetime. In renal transplant patients, because of treatment with immunosuppressive agents, BK viruria is a serious complication that is growing in prevalence. BK viruria may eventually lead to loss of the kidney graft, or to uncontrolled bleeding in the bladder.